Using Riboflavin to Benefit Gut Health

Abstract

Riboflavin may have beneficial effects in supporting intestinal health in healthy individuals. Specifically, riboflavin may relieve diarrhea or constipation, regulate bowel frequency, and regulate bowel urgency. Depending on dosage, the daily intake of riboflavin (taken through diet and dietary supplements) exceeds the RDA.

Description

Detailed Description of the Invention

[0001] The present invention relates to the use of riboflavin to regulate bowel movements, particularly in healthy individuals suffering from constipation and / or diarrhea.

[0002] [background] Mild functional gastrointestinal disorders, characterized by abdominal pain and discomfort, changes in bowel habits, primarily constipation or diarrhea, and urgency to move bowels, are widespread. Although these disorders are not fatal, these symptoms can nevertheless significantly affect the quality of life of millions of people worldwide. Chronic constipation affects approximately 12% of the world's population, and the prevalence of irritable bowel syndrome is approximately 11% worldwide. The public health costs of mild functional gastrointestinal disorders are substantial due to visits to primary care providers, prescription and over-the-counter medications, and missed work.

[0003] The causes of functional gastrointestinal disorders are still not fully understood, but there are some promising clues. Chronic inflammation is involved, especially in the intestinal mucosa. Certain genes appear to increase the risk of developing gastrointestinal disorders. Dysfunction of the gut-brain axis may also be important. Furthermore, the gut microbiota may help suppress inflammation and maintain the integrity of the intestinal epithelium, thus improving gut barrier function and potentially playing a central role in conditions such as irritable bowel syndrome.

[0004] It would be desirable to provide a dietary supplement or pharmaceutical product that could aid in regulating bowel activity in healthy individuals who do not experience constipation and / or diarrhea, as well as those who do.

[0005] [Detailed Description of the Invention] In accordance with the present invention, it has been discovered that a correlation exists between riboflavin intake and bowel regulation (especially in certain groups of people, such as those who are healthy but experience either diarrhea or constipation): with increasing riboflavin intake, the most common stool type changed to a more normal type and away from diarrhea or constipation (Figure 1), bowel frequency was more likely to be normal (Figure 2), and bowel urgency became normal as riboflavin intake increased (Figure 4).

[0006] Thus, one embodiment of the present invention is a method of promoting gut health comprising administering an effective amount of riboflavin to a healthy individual experiencing either diarrhea or constipation or at risk of experiencing diarrhea or constipation. Another embodiment of the present invention is the use of riboflavin in the manufacture of a medicament or dietary supplement or food product for promoting gut health in a healthy individual experiencing either diarrhea or constipation or at risk of experiencing diarrhea or constipation. Another embodiment is the non-therapeutic use of riboflavin for promoting gut health in a healthy individual experiencing diarrhea or constipation.

[0007] Another embodiment of the present invention is a method of alleviating symptoms of diarrhea or constipation experienced by a healthy individual, comprising administering an effective amount of riboflavin to a person in need thereof. Similarly, another embodiment is the non-therapeutic use of riboflavin to alleviate symptoms of diarrhea or constipation experienced by a healthy individual. Yet another embodiment is the use of riboflavin in the manufacture of a medicament or dietary supplement or food product to alleviate symptoms of diarrhea or constipation in a healthy individual.

[0008] Another embodiment of the invention is a method of regulating bowel frequency in a healthy individual comprising administering riboflavin to a healthy individual experiencing or at risk of experiencing abnormal bowel frequency. Another embodiment is the non-therapeutic use of riboflavin to regulate bowel frequency in a healthy individual. Another embodiment is the use of riboflavin in the manufacture of a pharmaceutical product, dietary supplement, or food product to regulate bowel frequency in a healthy individual.

[0009] Another embodiment of the present invention is a method for normalizing bowel urgency comprising administering an effective amount of riboflavin to a healthy individual in need of normalizing bowel urgency. Another embodiment is a non-therapeutic use of riboflavin for normalizing bowel frequency in a healthy individual. Another embodiment is the use of riboflavin for the manufacture of a medicine, food, or dietary supplement for normalizing bowel frequency in a healthy individual.

[0010] Another embodiment of the present invention is a method for normalizing stool type in a healthy individual, comprising administering an effective amount of riboflavin to a healthy individual in need thereof. Another embodiment is a non-therapeutic use of riboflavin for normalizing stool type in a healthy individual. Another embodiment is the use of riboflavin in the manufacture of a medicine, food, or dietary supplement for normalizing stool type in a healthy individual.

[0011] [Definition] As used throughout the specification and claims, the following definitions apply: "Promoting gut health" means supporting normal function of the gut (e.g., achieving normal bowel frequency and consistency).

[0012] "Mild functional gastrointestinal disorder" means a disorder of the function of the gastrointestinal tract (excluding irritable bowel syndrome) that results in an alteration in bowel habits that causes mild discomfort and is not due to structural or biochemical abnormalities. Some of the factors that contribute to the GI tract and its motility include: eating a low-fiber diet, lack of exercise, traveling, or other changes in daily life, consuming large amounts of dairy products, stress, resisting the urge to move a bowel, resisting the urge to move a bowel due to the pain of hemorrhoids, excessive use of laxatives / stool softeners that can weaken the intestinal muscles, taking antacids that contain calcium and / or aluminum, taking medications that are known to have such effects (certain antidepressants, iron supplements, and some narcotics), and pregnancy.

[0013] "Healthy individual" means an individual who has not been diagnosed with a disease or condition characterized by constipation or diarrhea (e.g., irritable bowel syndrome (IBS), Crohn's disease, sprue, or the like). Healthy individuals may experience constipation or diarrhea that is not IBS, Crohn's disease, or sprue (mild functional gastrointestinal disorders). [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 is a graph showing self-reported stool type and quartiles of riboflavin intake. [Diagram 2] Percentage of US adults aged 19 years and older with self-reported normal bowel frequency by quartile of riboflavin intake. [Diagram 3] Self-reported bowel movement frequency and total riboflavin intake stratified by dietary fiber intake in US adults aged 19 years and older. Data are means. [Figure 4] Total riboflavin intake: According to percentages for US adults aged 19 years and older and self-reported urgency to defecate.

[0015] [Dosage] The amount of riboflavin that should be taken by an adult per day according to the present invention is an amount greater than 3.1 mg. The currently recommended daily amount (RDA) for healthy individuals ranges from 1.1 to 1.6 mg per day, depending on gender and pregnancy and lactation status, which is usually obtained from a balanced diet. Thus, the total amount of riboflavin taken per day (greater than 3.1 mg) includes both the amount taken in the diet and the amount supplemented. Thus, in one embodiment of the present invention, an "effective amount" is a supplement of at least 1 to 5 mg per day, which should be taken in addition to the RDA of 1.1 to 1.6 mg per day obtained from a normal diet. In a preferred embodiment, the amount in the dietary supplement is at least 1 to 3 mg more than the RDA, more preferably at least 1.5 to 2 mg more than the RDA. There is no upper limit to the amount of riboflavin that can be taken, because unused riboflavin is excreted from the body. In controlled clinical trials, no side effects were observed even at very high doses.

[0016] As such, riboflavin may be taken in a single dose or divided into several doses taken throughout the day.

[0017] [Combination of riboflavin and dietary fiber] Another embodiment of the present invention is a combination of riboflavin and dietary fiber. Increased frequency of bowel movements was mainly observed when dietary fiber intake was in the top three-quarters (more than 9g / day). Most nutritionists would consider a daily intake of 9 grams of dietary fiber to be low, and would point out at least 18 grams per day as a recommended amount. Therefore, one embodiment of the present invention is a daily dosage of a dietary supplement that includes an effective amount of riboflavin in combination with sufficient dietary fiber, together or separately, to make a person's daily intake at least 18 grams per day.

[0018] The amount of additional dietary fiber required will of course depend on the individual's intake of dietary fiber from food. Our research has shown that the median intake is 13 grams per day. Thus, a preferred embodiment is at least 13 grams of dietary fiber per day plus at least 5 grams of dietary fiber per day, and in other preferred embodiments, the amount of dietary fiber supplemented is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 grams per day, so that the total amount of dietary fiber is at least 18 grams per day. For individuals with dietary fiber intake below the median, the dosage may be 8 grams per day. Conversely, for individuals with dietary fiber intake above the median, the dosage may be 2 grams per day.

[0019] Therefore, another embodiment of the present invention is a composition comprising an effective amount of riboflavin in combination with dietary fiber. The amount of dietary fiber is at least 4 grams of dietary fiber per day, and preferably at least 5 grams. Numerous dietary fiber supplement sources are commercially available.

[0020] Some examples of dosages of riboflavin and dietary fiber in dietary supplements are as follows: A. 1 to 2 mg of riboflavin and 5 grams of dietary fiber for people consuming the full RDA of riboflavin and the median amount of dietary fiber per day. B. For individuals consuming the full RDA amount of riboflavin and less than the median amount of dietary fiber per day, 1 to 2 mg of riboflavin and 8 grams of dietary fiber. C. 1 to 2 mg of riboflavin and 3 grams of dietary fiber for individuals consuming the full RDA amount of riboflavin and higher than the median amount of dietary fiber per day.

[0021] [Dosage form] The dosage form may be any convenient oral dosage form. For the purposes of the present invention, the riboflavin and / or dietary fiber are suitably provided in a composition for oral administration, which may be a solid or liquid galenic formulation, dietary composition, pharmaceutical product, or food. Examples of solid galenic formulations are tablets, capsules (e.g., hard-shell or soft-shell gelatin capsules), pills, sachets, powders, granules, and the like, which contain the riboflavin and / or dietary fiber together with a conventional galenic carrier. Any conventional carrier material may be used. The carrier material may be an organic or inorganic inert carrier material suitable for oral administration. Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, and the like. Additional additives (e.g., flavorings, preservatives, stabilizers, emulsifiers, buffers, and the like) may be added according to the practice of pharmaceutical compounding. Additional active ingredients for co-administration with the riboflavin and / or dietary fiber may be administered together in a single composition or in individual dosage units. The dietary composition comprising riboflavin and / or dietary fiber may be a beverage, an instant beverage, or a dietary supplement.

[0022] In order to better illustrate the present invention, the following non-limiting examples are presented.

[0023] [Example] [Study cohort] Data were obtained from NHANES, a representative survey measuring the health and nutritional status of the non-hospitalized population of the United States. The study protocol was reviewed and approved by the National Center for Health Statistics Research Ethics Review Board (Protocol #2005-2006). Ethics review of the protocols used in the NHANES protocol is conducted annually, and ongoing changes are submitted through an amendment process. All participants provided written informed consent prior to participation. Potentially identifying information of participants was removed prior to publication of the data.

[0024] For this analysis, data were selected from adults aged 20 years or older during the survey years 2005-2010. Participants were selected using a complex, multistage probability sampling design to generate a representative sample. Demographic information (gender, age, ethnicity, education, poverty-income ratio) was obtained by self-report during an interview conducted by a trained interviewer in the participant's home. Questions about gut health were administered to adults aged 20 years or older at a mobile testing center using a computer-assisted personal interview system. Dietary assessment was performed using two 24-hour dietary recalls, one in person at the mobile testing center and the second by telephone 3-10 days after the dietary interview, but not on the same day of the week. Pregnancy status was determined by self-report in women aged 20-44 years, and negative responses were confirmed by a urine pregnancy test. Riboflavin intake from dietary supplements in the 2005-2006 survey cycle was calculated based on reported dietary supplement use over the past 30 days and by modifying the program used to estimate calcium intake from dietary supplements over these survey years. For the 2007-2010 survey cycle, total dietary supplement intake from the 30-day questionnaire was also used, based on the total reported in the dataset. Subjects with self-reported inflammatory bowel disease were excluded.

[0025] The gut health questionnaire in the 2005-2006 and 2007-2008 survey cycles consisted of six questions: four related to the assessment of the Fecal Incontinence Severity Index (Rockwood,et al 1999 Dis Colon Rectum 42,1525-1532), one question asked participants about their self-reported weekly frequency of bowel movements, and one question related to normal stool type on the Bristol Stool Scale (Lewis et al 1997 Scand J Gastroenterol 32: 920-924). The Fecal Incontinence Intensity Score (FISI) was calculated and divided into four categories using the RANK procedure to obtain approximately equal categories. In the 2009-2010 survey cycle, questions were added regarding urgency to defecate, incidence of constipation and diarrhea in the past year, and use of laxatives in the past 30 days.

[0026] [Statistical analysis] Statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at 0.05. Means and percentages were adjusted to be representative of the US population using sample weights for the day 2 dietary data set for analyses including riboflavin intake and Mobile Examination Center sample weights for other analyses (Table 1), and taking into account the complex survey design using the SURVEYFREQ and SURVEYMEANS procedures.

[0027] We divided the parameters of the linear regression model into chunks representing socio-demographic and lifestyle factors, similar to the approach used by Sternberg et al. 2013 J.Nutr 143:948S-956S, and investigated the relationship between riboflavin intake from diet and / or dietary supplements and defecation frequency using factors related to gut health identified by Mitsuhashi et al. 2017 Am J Gastroenterol 10.1038 / ajg.2017.213. Gender, ethnicity, education, age (continuous), and poverty income ratio (PIR, continuous) were included in the socio-demographic chunks, and vigorous physical activity in the past 30 days (Y / N), dietary supplement use (Y / N), dietary fiber and fluid intake (continuous), self-reported thyroid problems (Y / N), and prescription medication use (1 or less vs. 2 or more) were included in the diet and health chunks.

[0028] Stepwise linear regression model selection was first performed with the REG procedure to identify consistently non-significant predictors in chunks of the model, which were then combined into a full model, based on which vigorous physical activity and dietary supplement use were excluded. A final linear regression using the significant predictors was performed using SURVEYREG to generate accurate variance estimates that accounted for the complex study design.

[0029] [result] A total of 17,110 adults aged 20 years or older were selected from the 2005-2010 NHANES survey cycles to create the analytic dataset.

[0030] Table 1 presents demographic parameters, socioeconomic parameters, pregnancy status, dietary intake, and use of dietary supplements, laxative and prescription drug use, as well as gut health parameters. Laxative use was recorded in only one third of the data set (survey period 2009–2010). We found no significant differences between survey years.

[0031] [Table 1]

[0032] [Table 2]

[0033] [Table 3]

[0034] [Table 4]

[0035] The differences between riboflavin from dietary sources and from supplements are reported in Table 2. In general, riboflavin intake from supplements is higher and shows greater variability than from food (see Supplementary Table S1 above).

[0036] [Table 5]

[0037] [Table 6]

[0038] Women had lower dietary riboflavin intakes compared with men, but were more likely to use riboflavin-containing dietary supplements and had similar total riboflavin intakes. Those aged 70 years or older had the lowest dietary riboflavin intakes.

[0039] Non-Hispanic whites had the highest mean riboflavin intake from food, non-Hispanic blacks had the lowest, and Mexican Americans were in between. Mexican Americans had the highest total riboflavin intake.

[0040] As poverty income ratios (PIRs) increased (indicating higher household income), riboflavin intakes from food, supplements, and total increased. A similar relationship was found for education level, with higher levels of education associated with higher riboflavin intakes from food, supplements, and total.

[0041] Similarly, there was a positive correlation between riboflavin intake and dietary fiber intake, with Pearson correlation coefficients for dietary fiber intake and food, supplement, and total riboflavin intakes being 0.461 (p<0.0001), 0.0867 (p<0.0001), and 0.125 (p<0.0001), respectively.

[0042] Total fluid intake (including all fluids from food and drinking water, including tap water and bottled water) also increased with increasing riboflavin intake.

[0043] Riboflavin intake from food was significantly higher in dietary supplement users, as was total riboflavin intake.

[0044] Individuals with low (below the median) use of prescription drugs had higher riboflavin intakes from food, but there were no differences in riboflavin intakes from dietary supplements and total riboflavin intake.

[0045] There appeared to be an increasing trend between riboflavin intake and FISI scores, but this was not significant.

[0046] The results of the linear regression are shown in Table 3.

[0047] [Table 7]

[0048] In the crude model, there was a significant positive association between dietary, supplemental, and total riboflavin intake and defecation frequency. However, after adjustment for sociodemographic and dietary and lifestyle cofactors, this association was not significant for dietary riboflavin, whereas the fully adjusted model showed a significant positive association between dietary and total riboflavin intake and defecation frequency.

[0049] Bristol Stool Type according to quartiles of riboflavin intake is shown in Figure 1. With increasing riboflavin intake, stool types 2 (slow transit time) and 5 (soft fluid stool) decreased and type 4 (normal bowel movement) increased.

[0050] Normality of bowel frequency, defined as 3 to 21 bowel movements per week according to quartiles of riboflavin intake, is shown in Figure 2 .

[0051] As riboflavin intake increases with respect to food and total riboflavin, the proportion of the population with normal bowel patterns increases. Since there was a particularly high correlation between food and total riboflavin intake, Figure 3 shows the relationship between total riboflavin intake and bowel frequency stratified by quartiles of dietary fiber intake. As riboflavin intake increases, bowel frequency increases, and stratification with respect to dietary fiber intake shows a similar relationship when dietary fiber intake is high compared to the median. Interestingly, this relationship is only significant for the top two quartiles of dietary fiber intake; at low dietary fiber intake (below the median), there is no significant relationship between riboflavin intake and bowel frequency.

[0052] Figure 4 shows the association between bowel urgency and riboflavin intake. In the top two quartiles of riboflavin intake, there was a significant increase in the number of respondents reporting that this occurred "rarely," which was likely due to a non-significant decrease in both those reporting that bowel urgency occurred "never" and those reporting that it occurred more frequently than "rarely."

[0053] [Consideration] Our results show that riboflavin intake from both food and supplements correlates with improved subjective gut health parameters. Increased bowel movement frequency with higher riboflavin intake corresponds to an increased proportion of participants with normal stool type (type 4) and a greater lack of subjective urgency to defecate. Increased bowel movement frequency does not imply a decrease in normality of bowel movement frequency, and in higher intake quartiles, a higher proportion of subjects reported being within the "3 and 3" metric of normal frequency.

[0054] In this dataset, a clear correlation is found between dietary fiber and riboflavin intake. The best dietary sources of riboflavin (organ meats, eggs, and dairy products) do not contain dietary fiber, but high-fiber grain products (especially whole-grain and fortified breakfast cereals) contribute significantly to total riboflavin intake. In addition, higher socioeconomic status is associated with higher intakes of dietary fiber and is also associated with better dietary quality, which in turn correlates with intake.

[0055] Crude and adjusted linear regressions showed significant associations between bowel movement frequency and riboflavin intake from dietary supplements and total (Table 3). Linear regression adjusted models included dietary fiber as a dietary / healthy chunk regressor to account for potential confounding. The relationship between bowel movement frequency and riboflavin intake, stratified for dietary fiber intake, was examined in Figure 3. Figure 3 shows that bowel movement frequency increased only with riboflavin intake in the top two quartiles of dietary fiber intake.

[0056] Our analysis showed that riboflavin intakes are generally above the DRI and there is little evidence of inadequate riboflavin intake in the United States. Fulgoni et al. 2011 J.Nutrition 141 1847-51 found that less than 5% of the population has inadequate riboflavin intake.

[0057] The effect of riboflavin on gut health parameters was seen above the median riboflavin intake of 2.1 mg / day, especially in the highest quartile of riboflavin intake (>3.1 mg / day). In subjects consuming diets with sufficient riboflavin, 1-3% of the recovered urinary metabolites were microbial riboflavin degradation products, indicating that unabsorbed dietary riboflavin reaches the large intestine where it is metabolized by gut microbes. See Chastain, 1987 Am J Clin Nutrition 46 830-834. The amount of riboflavin absorbed is dependent on the administered dose, with absorption increasing linearly up to a saturating dose of approximately 30 mg (Powers 2003 Am J Clinical Nutrition 77:1352-1360). The amount of absorption is lower when riboflavin is taken in the fasting state compared to when it is taken with a meal, possibly due to the faster transit time through the proximal small intestine, where most absorption occurs, on an empty stomach. Thus, the higher the supplemental dose, the more will remain unabsorbed in the intestinal lumen and therefore be available to the gut microbiota. Without wishing to be bound by theory, it is believed that the relatively higher amount of riboflavin reaching the colon from the supplement may explain why the significance of dietary riboflavin, but not dietary supplements and total riboflavin, is lost upon adjustment for dietary / health confounders.

[0058] To our knowledge, this is the first study to report the association between riboflavin intake and gut health parameters in a human observational study. Strengths of our study include the large sample size and the wide range of parameters tested as part of the linear regression model. The use of two 24-hour dietary recalls is the gold standard for dietary assessment in large samples.

[0059] In summary, with increasing riboflavin intake, the most common stool type changed to a more normal type and away from diarrhea or constipation (Figure 1), bowel frequency was more likely to be normal (Figure 2), and bowel urgency became normal as riboflavin intake increased (Figure 4).

Claims

1. the below described: A) Normalization of diarrhea or constipation; B) Regulating the frequency of bowel movements; and C) Regulating the urgency of bowel movements 1. A composition comprising riboflavin (excluding probiotics, dietary fiber and chlorella hot water extract) for non-therapeutic use in promoting intestinal health parameters in healthy individuals selected from the group consisting of:

2. The composition described in claim 1, wherein the composition is a dietary or dietary supplement, and the total amount of riboflavin ingested through the diet and dietary supplement exceeds the recommended daily amount (RDA) for healthy individuals.

3. The composition described in claim 1 or 2, wherein the composition is a dietary supplement and the amount of riboflavin provided in the dietary supplement is at least 1 to 5 mg.

4. The composition described in claim 1 or 2, wherein the composition is a dietary supplement and the amount of riboflavin provided in the dietary supplement is at least 1 to 3 mg.

5. The composition described in claim 1 or 2, wherein the composition is a dietary supplement and the amount of riboflavin provided in the dietary supplement is at least 1.5 to 2 mg.

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